AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Background

The free-living amoebae that cause human infections include Acanthamoeba, Naegleria, Balamuthia mandrillaris, and Sappinia diploidea. All 4 genera cause CNS infections that are frequently fatal. These amoebae are distinct from other pathogenic protozoa. They all have a free-living existence, have no human carrier state (which is important in disease transmission), have a limited relationship with the spread of infection and poor sanitation, and have no insect vector.

The pathogenic species of Acanthamoeba include Acanthamoeba castellanii, Acanthamoeba polyphaga, Acanthamoeba culbertsoni, Acanthamoeba palestinensis, Acanthamoeba astronyxis, Acanthamoeba hatchetti, Acanthamoeba rhysodes, Acanthamoeba divionesis, Acanthamoeba quna, Acanthamoeba lugdunensis, and Acanthamoeba griffini. The life cycle consists of 2 stages: a trophozoite (which is 14-40 µm in diameter) and a cyst (which has a double-layered wall with a diameter of 12-16 µm).

Acanthamoeba was first established as a cause of human disease in the 1970s. This genus causes 3 clinical syndromes: granulomatous amebic encephalitis (GAE), disseminated granulomatous amebic disease (eg, skin, sinus, and pulmonary infections), and amebic keratitis. Patients who develop GAE or disseminated disease are usually immunocompromised, whereas those with amebic keratitis are usually immunocompetent. The outcomes of disseminated disease and GAE are poor, and treatment strategies are not well defined; Acanthamoeba keratitis is a sight-threatening disease that has favorable prognosis when diagnosed and treated early in the disease course.

Pathophysiology

Acanthamoeba keratitis occurs in patients who sustain minor corneal trauma; this is usually associated with wearing contact lenses. Amoebae can be introduced through environmental exposures, including swimming while wearing contact lenses or using contaminated contact lens solutions, especially homemade solutions. Rare reports cite radial keratotomy as preceding this infection.

GAE usually develops after the hematogenous spread of the amoebae from pulmonary or skin lesions to the CNS. Alternatively, amoebae may enter via the olfactory epithelium.

Disseminated disease may begin in the sinuses, skin, or lungs and disseminate from these locations to other sites, including the brain, leading to GAE.

Epidemiology

Acanthamoeba are ubiquitous organisms and have been isolated from soil, water (including natural and treated water), air, and dust. Most persons appear to have been exposed to this organism during their lifetime, as 50-100% of healthy people have serum antibodies directed against Acanthamoeba; studies have also demonstrated that this amoeba can be cultured from the pharynges of healthy persons. Acanthamoeba has caused disease worldwide, including the United States, Europe, Australia, Africa, and South America.

Acanthamoeba keratitis typically occurs in healthy persons, with over 1300 cases described in the literature. Most cases occur in people who wear contact lenses. Keratitis has been associated with wearing nondisposable contact lenses, the use of homemade sodium chloride solution to clean the lenses, and wearing lenses while swimming. The isolation of Acanthamoeba from swimming pool water is not unusual. The presence of Acanthamoeba in swimming pool water and the bacteriologic quality of the water have no correlation. Acanthamoeba cysts are very resistant to chlorine. A higher percentage of isolates from swimming pools have been shown to be pathogenic than those isolated from natural fresh water.

Despite the widespread existence of Acanthamoeba, GAE usually occurs among immunocompromised persons, including those with AIDS, transplant recipients, patients with cancer receiving chemotherapy, and those with systemic lupus erythematosus, steroid use, diabetes mellitus, malnutrition, or liver disease. Likewise, persons with disseminated disease without CNS involvement are usually immunocompromised; this condition is seen most commonly among patients with AIDS who have low CD4 counts (eg, <200 cells/µL). In unusual cases, disseminated disease may occur among immunocompetent children and adults. The incidence of GAE and disseminated disease appears to be rising, likely mirroring the increase number of persons worldwide who are living with immunocompromising conditions. To date, more than 100 cases of GAE have been described.

Frequency

United States

Keratitis cases substantially increased in the 1980s with the introduction of disposable soft contact lenses. Some evidence shows that the rate has subsequently declined, especially with the introduction of multipurpose cleaning solutions. The estimated rate of Acanthamoeba keratitis is 1 per 250,000 people in the United States, although rates vary among studies: from 1.65-2.01 per million population up to 1 per 10,000 people who wear contact lenses.

GAE and disseminated Acanthamoeba disease are very rare, but rates may be increasing given the rising number of persons living with immunocompromising conditions. More than 100 cases of GAE have been described to date.

International

Acanthamoeba can cause keratitis, GAE, and disseminated disease worldwide. Data on the incidence rates of these infections internationally are not available since it is not a reportable disease.

Mortality/Morbidity

• Keratitis is a local infection that does not lead to systemic infection or death but may be complicated by cataracts, hypopyon, and increased intraocular pressure and may threaten sight.
• GAE has a very high mortality rate of nearly 100%. Survivors of GAE have been described; these patients were treated with combination antimicrobial therapies. Disseminated disease also has a high mortality rate, but it is lower than GAE if CNS involvement does not occur.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

History

• Keratitis
• • Contact lens use with history of improper cleaning, use of homemade sodium chloride solution, and swimming in fresh water or a swimming pool, especially while contact lenses are worn (Rarely, this infection develops after radial keratotomy. The incubation period is a few days. Keratitis typically begins with a foreign-body sensation followed by pain, tearing, photophobia, blepharospasm, and blurred vision. Patients may have periods of symptom remission with a waxing and waning course.)
  • Foreign-body sensation
  • Severe pain
  • Tearing
  • Blepharospasm
  • Photophobia
  • Blurred vision
• Granulomatous amebic encephalitis (GAE) is a subacute diffuse meningoencephalitis, usually with an insidious onset. The incubation period is unknown but is probably weeks to months. The duration of illness until death ranges from 7-120 days (average, 39 d). Patients with GAE may have concurrent sinus, lung, or skin disease. Most patients present with focal neurologic deficits; other symptoms are as follows:
• • Mental status changes (86%)
  • Seizures (66%)
  • Hemiparesis (53%)
  • Fever (53%)
  • Headache (53%)
  • Meningismus (40%)
  • Visual disturbances (26%)
  • Ataxia (20%)
  • Nausea and vomiting
  • Hallucinations
  • Personality changes
  • Photophobia
  • Sleep disturbances
• Skin disease may predate the onset of CNS manifestations by weeks to months and may include ulcers, nodules, or subcutaneous abscesses. Disseminated disease without CNS involvement may manifest as skin lesions, sinusitis, pneumonitis, or a combination. Other unusual manifestations of Acanthamoeba infections have included osteomyelitis, adrenalitis, and vasculitis.

Physical

• Keratitis
• • Conjunctivitis or conjunctival hyperemia
  • Corneal ulceration
  • Lid edema
  • A characteristic corneal ring stromal infiltrate
  • Anterior uveitis of fluctuating severity
  • Increased intraocular pressures
  • Hypopyon
  • Cataract formation
• Granulomatous amebic encephalitis
• • Altered mental status
  • Ataxia
  • Fever
  • Hemiparesis
  • Cranial nerve deficits
  • Meningismus, Babinski sign, and Kernig sign
  • Diplopia, photophobia
  • Coma
  • Concurrent skin lesions, sinus tenderness, or pulmonary rales
• Disseminated disease without GAE may manifest as skin lesions that are typically hard erythematous nodules or skin ulcers. Other presentations of disseminated disease include pneumonitis and sinusitis.

Causes

• Keratitis
• • Wearing contact lenses
  • Using homemade sodium chloride solutions to clean contact lenses
  • Wearing contacts while swimming
  • Cleaning contact lenses less frequently than recommended by the manufacturer
• Granulomatous amebic encephalitis and disseminated disease: Acanthamoeba is ubiquitous; most persons are exposed to this organism. Although rare cases have been described in immunocompetent adults and children, the main risk factors for the development of disease include immunocompromising conditions and factors associated with immunosuppression, such as the following:
• • AIDS
  • Liver disease
  • Transplantation
  • Diabetes mellitus
  • Steroids
  • Systemic lupus erythematosus
  • Cancer that requires chemotherapy
  • Malnutrition

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Other Problems to be Considered

Keratitis
Bacterial keratitis
Viral (herpes, varicella) keratitis
Fungal keratitis

GAE
Naegleria, Balamuthia infections
Epilepsy
Brain tumor or CNS lymphoma
Numerous other causes of aseptic meningitis or encephalitis

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Lab Studies

• Keratitis
• • Diagnosis requires a high index of suspicion; an early diagnosis is critical for the retention of good visual acuity.
  • Acanthamoeba trophozoites or cysts can be demonstrated with corneal scrapings or a biopsy sample via wet mount, stains, histopathologic examination, or culture.
  • • Motile trophozoites may be seen in a wet-mount preparation.
    • Stain corneal scrapings with calcofluor white (stains cyst walls) and examine specimen with fluorescent microscopy.
    • Cysts and trophozoites can be seen with a number of stains, including hematoxylin and eosin (H&E), Giemsa, and Wright.
    • Amoebae may be cultured with a non-nutrient agar (NNA) overlaid with Escherichia coli.
  • Conduct polymerase chain reaction (PCR) of biopsy specimens.
  • If corneal specimens are unremarkable, consider culturing the contact lenses and saline solution for Acanthamoeba.
  • Suprainfecting bacteria can complicate the diagnosis; isolation of a bacterial pathogen does not exclude Acanthamoeba as the cause of the keratitis.
• Granulomatous amebic encephalitis
• • This condition is diagnosed postmortem or via brain biopsy.
  • Cerebrospinal fluid examination reveals an increased number of white blood cells (up to 800 cells/µL, primarily lymphocytes), elevated protein levels, and decreased glucose levels.
  • Examining the CSF for organisms is of very low yield.
• Disseminated disease: Perform biopsy and culture areas of involvement.

Imaging Studies

• Granulomatous amebic encephalitis
• • CT scan should be obtained before a lumbar puncture is performed to ensure that this procedure is not contraindicated because of the herniation risk.
  • Findings on CT scan include multiple nonenhancing lesions in the cerebral cortex.

Procedures

• Keratitis: Obtain eye scrapings or biopsy samples.
• Granulomatous amebic encephalitis
• • Perform lumbar puncture and brain biopsy.
  • Lumbar puncture may be contraindicated if signs of increased intracranial pressure are present.
  • If skin lesions are present, perform skin biopsy.
• Disseminated disease: Obtain biopsy samples of the involved sites (eg, skin, sinuses).

Histologic Findings

In keratitis, amebic cysts and trophozoites are found within the cornea. An acute or mixed inflammatory infiltrate may contain giant cells. Corneal revascularization may occur.

Individuals with GAE have moderate-to-severe cerebral edema. Necrotizing granulomas that contain perivascular trophozoites and cysts are usually located in the cerebellum, mid brain, and brain stem. Multinucleated giant cells may be present within the granulomas. Granulomas are usually noted among immunocompetent patients. On biopsy specimens, angiitis with perivascular cuffing with lymphocytes may be seen. The leptomeninges are spared except when they directly overlie areas of cortical involvement.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical Care

Medical therapy for Acanthamoeba infection is not well established. Listed below are treatments that have been reported in the literature.

• Keratitis
• • Successful treatment of keratitis consists of early diagnosis and aggressive surgical and medical therapies.
  • Medical treatment consists of topical antimicrobial agents, which can achieve high concentrations at the site of the infection.
  • Because the cyst form may be highly resistant to therapy, a combination of agents is generally used.
  • Many authorities recommend a combination of propamidine 0.1% and miconazole nitrate 1% with neomycin. Others suggest a combination of a diamide (propamidine isethionate or hexamidine) with a cationic antiseptic (polyhexamethylene biguanide [PHMB] or chlorhexidine).
  • These topical antimicrobials are administered immediately after corneal debridement every hour. These agents then are continued hourly during waking hours for 3 days. The frequency then is reduced to every 3 hours. Two weeks may be required before a response is observed, and the total duration of therapy is a minimum of 3-4 weeks. Some advocate treating for 6-12 months. When therapy is discontinued, close observation is warranted to rule out recurrent disease.
  • No clear consensus exists about use of steroids. Most authorities recommend that steroid use is probably best avoided. Patients receiving steroids should continue antiamebic therapy for several weeks after the steroids are stopped.
  • Rabinovitch and coworkers (1991) showed that steroid use was significantly greater among patients in whom medical therapy failed than in those whose medical therapy was successful.
  • A more recent study by Park et al (1997) revealed no difference in response to medical therapy in patients who used topical steroids compared with those who did not. However, in this study, patients treated with topical steroids required longer duration of medical therapy (38.5 wk vs 20 wk).
• Granulomatous amebic encephalitis
• • Treatment is not standardized and is limited. Most use a combination of therapies for the treatment of GAE, which should be urgently administered.
  • In vitro and in vivo data suggest that the following medications have activity against Acanthamoeba:
  • • Ketoconazole, itraconazole, fluconazole
    • Pentamidine
    • Hydroxystilbamidine
    • Paromomycin
    • Polymyxin
    • Colistin
    • Trimethoprim-sulfamethoxazole
    • Sulfadiazine
    • Flucytosine
    • Clotrimazole
    • Phenothiazines
    • Rifampin
  • Two immunocompetent children survived with treatment that consisted of ketoconazole, rifampin, and trimethoprim-sulfamethoxazole.
  • Another potential regimen is intravenous pentamidine, topical chlorhexidine gluconate, and 2% ketoconazole cream, followed by oral itraconazole.
• Disseminated disease: A case that involved only the skin was treated with intravenous pentamidine, topical chlorhexidine gluconate, and 2% ketoconazole cream, followed by oral itraconazole.

Surgical Care

• Keratitis: The abnormal epithelium is débrided. Penetrating keratoplasty may be necessary in cases that do not respond to medical therapy.

Consultations

• Keratitis
• • Infectious diseases specialist
  • Ophthalmologist
• Granulomatous amebic encephalitis and disseminated disease
• • Infectious diseases specialist
  • Neurologist

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

The goals of pharmacotherapy are to eradicate the infection, to reduce morbidity, and to prevent complications.

Drug Category: Antifungals

The mechanism of action of these agents may involve an alteration of RNA and DNA metabolism or an intracellular accumulation of peroxide that is toxic to the fungal cell.

Drug Name	Itraconazole (Sporanox)
Description	Synthetic triazole antifungal agent that slows fungal cell growth by inhibiting cytochrome P-450–dependent synthesis of ergosterol, a vital component of fungal cell membranes.
Adult Dose	200-400 mg PO qd
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Antacids may reduce absorption of itraconazole; edema may occur with coadministration of calcium channel blockers (eg, amlodipine, nifedipine); hypoglycemia may occur with sulfonylureas; may increase tacrolimus and cyclosporine plasma concentrations when high doses are used; rhabdomyolysis may occur with coadministration of HMG-CoA reductase inhibitors (lovastatin or simvastatin); coadministration with cisapride can cause cardiac rhythm abnormalities and death; may increase digoxin levels; coadministration may increase plasma levels of midazolam or triazolam; phenytoin and rifampin may reduce itraconazole levels (phenytoin metabolism may be altered)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in hepatic insufficiencies

Drug Name	Pentamidine (Pentam-300, Pentacarinat, NebuPent)
Description	Inhibits growth of protozoa by blocking oxidative phosphorylation and inhibiting incorporation of nucleic acids into RNA and DNA, causing inhibition of protein and phospholipid synthesis.
Adult Dose	4 mg/kg/d IV; dose reduction to 3 mg/kg often is employed after first 3 d to manage toxicity
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in diabetes mellitus, hypertension or hypotension, hepatic dysfunction, hypoglycemia, leukopenia, and thrombocytopenia

Drug Name	Flucytosine (Ancobon)
Description	Converted to fluorouracil after penetrating fungal cells. Inhibits RNA and protein synthesis. Active against Candida and Cryptococcus and generally used in combination with amphotericin B.
Adult Dose	100 mg/kg/d PO divided qid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Amphotericin B may increase toxicity of flucytosine; cytosine may inactivate flucytosine
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in bone marrow suppression; adjust dose in renal impairment

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Deterrence/Prevention

• Keratitis
• • Avoid homemade sodium chloride solutions and swimming while wearing contacts.
  • Follow manufacturer's guidelines regarding cleaning contact lenses.
  • Heat disinfect or use benzalkonium-preserved saline for cleaning contact lenses.

Complications

• Keratitis
• • Hypopyon
  • Cataracts
  • Loss of vision
• Granulomatous amebic encephalitis
• • Seizures
  • Coma
  • Death

Prognosis

• Keratitis usually responds to medical therapy. The disease process may affect visual acuity.
• GAE has a high mortality rate of nearly 100%. Most cases are fatal in 7-120 days (mean, 39 d).
• Disseminated disease with skin involvement (no CNS disease) is associated with a mortality rate of 73%.

Patient Education

• Contact lens wearers should avoid homemade sodium chloride solutions and swimming while wearing contact lenses. Patients should consult manufacturer's guidelines regarding cleaning instructions.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical/Legal Pitfalls

• Keratitis
• • Failure to consider Acanthamoeba in the differential diagnoses of keratitis and to obtain the appropriate diagnostic studies to evaluate for this condition
  • Failure to instruct patients regarding proper lens-cleaning procedures
  • Failure to advise patients to avoid swimming with lenses
  • Failure to advise patients to not use homemade sodium chloride solutions

ACKNOWLEDGMENTS

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous coauthor William B. Harley, MD, to the development and writing of this article.

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

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Article Last Updated: Jun 2, 2006